Human natural killer cell recognition of cytomegalovirus

人类自然杀伤细胞对巨细胞病毒的识别

• 批准号: 8617610
• 负责人: William Hildebrand
• 金额: $ 20.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-16 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617610
• 关键词: Affinity; Antigens; Binding; Biological; Blood; Cells; Complex; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Disease; E protein; Foundations; Future; Generations; Goals; Hematopoietic stem cells; Human; Immune system; Individual; Infection; Infection prevention; KLRD1 gene; Life; Ligands; Major Histocompatibility Complex; Mass Spectrum Analysis; Measures; Medical; Morbidity - disease rate; Natural Killer Cells; Nature; Organ; Peptides; Persons; Population; Pregnancy; Prevention; Proteins; Risk; Solid; Stem cell transplant; T-Lymphocyte; Techniques; Testing; Tissues; Transplant Recipients; Vaccination; Virus; Woman; comparative; neonate; novel; novel therapeutics; peptide E (adrenal medulla); public health relevance; receptor; treatment strategy

Project Summary/Abstract Cytomegalovirus (CMV), which infects half of the US population, establishes a persistent infection for the life of the person and is of particular risk to solid organ and hematopoietic stem cell transplant patients and individuals with a compromised immune system. Natural killer (NK) cells, together with T cells, are required to control this persistent infection for the lifetime of the individual. We recently made the unexpected observation that human NK cells bearing a unique invariant activating CD94-NKG2C receptor can preferentially and specifically respond to CMV infection in the outbred human population. We had previously demonstrated that the CD94-NKG2C receptor recognizes HLA-E, an essentially non-polymorphic major histocompatibility complex protein that is expressed on all cells and tissues in the body. The expansion of CD94-NKG2C+ NK cells following CMV infection likely reflects the recognition of a peptide from CMV or the infected host cell expressed in the context of HLA-E. In this project, we propose to use a novel and elegant technique to determine the changes in the peptide repertoire of HLA-E in CMV-infected cells by creating soluble, secreted HLA-E molecules that can be easily purified for elution of bound peptides followed by comparative mass spectrometry. Aims of this project are: 1) To determine the nature of the peptides bound to HLA-E in uninfected versus CMV-infected cells. We will test the hypothesis that CMV-infected cells will demonstrate an altered HLA-E peptide repertoire, including the generation of HLA-E proteins displaying CMV-encoded peptides, as well as CMV-induced host-encoded peptides. 2) To measure the binding of CMV-induced HLA-E -peptide complexes for the activating CD94-NKG2C versus inhibitory CD94-NKG2A receptors and test the ability of these HLA-E-CMV-induced peptide complexes to stimulate primary human NK cells expressing the CD94-NKG2C receptor. Identifying high affinity or preferential HLA-E ligands for the CD94-NKG2C receptor will provide the foundation for future studies to characterize the biological consequences of recognition of these novel ligands. Vaccines for CMV are an unmet medical need and the identification of these novel CMV-induced HLA-E-peptide antigens may provide new therapeutic strategies for the treatment or prevention of CMV infection.

项目摘要/摘要 感染一半美国人口的巨细胞病毒（CMV）为生命而建立了持续的感染 该人，对固体器官和造血干细胞移植患者的风险特别风险 具有损害免疫系统的人。自然杀手（NK）细胞以及T细胞需要 控制个人的持续感染。我们最近做出了意外的观察 带有独特不变激活CD94-NKG2C受体的人NK细胞可以优先，并且 特别应对人口中的CMV感染。我们以前已经证明了 CD94-NKG2C受体识别HLA-E，这是一种本质上非造型的主要组织相容性 复杂的蛋白质在体内的所有细胞和组织上表达。 CD94-NKG2C+ NK的扩展 CMV感染后的细胞可能反映了CMV或感染宿主细胞的肽的识别 在HLA-E的背景下表达。在这个项目中，我们建议使用一种新颖而优雅的技术来 通过创建可溶性，分泌的CMV感染细胞中HLA-E肽库的变化 可以轻松纯化以洗脱结合肽，然后进行比较质量的HLA-E分子 光谱法。该项目的目的是：1）确定与HLA-E约束的肽的性质 未感染的与CMV感染的细胞。我们将检验以下假设，即CMV感染的细胞将证明 改变HLA-E肽库，包括显示CMV编码的HLA-E蛋白的产生 肽以及CMV诱导的宿主编码的肽。 2）测量CMV诱导的HLA-E的结合 - 激活CD94-NKG2C与抑制性CD94-NKG2A受体的肽复合物并测试 这些HLA-E-CMV诱导的肽复合物的能力刺激表达的原代人NK细胞 CD94-NKG2C受体。确定CD94-NKG2C受体的高亲和力或优先HLA-E配体 将为未来的研究提供基础，以表征认识这些的生物学后果 新颖的配体。 CMV的疫苗是未满足的医疗需求，并且鉴定了这些新型CMV诱导的 HLA-E肽抗原可以为治疗或预防CMV提供新的治疗策略 感染。